Genetic Risk Factor For Suicidal Behavior

描述(由申请人提供)：这项建议旨在识别和表征与自杀行为易感性有关的新基因变异。我们将通过对一个与此密切相关的染色体区域进行深入的后续研究，以及通过首次在外显子组范围内寻找与此表型相关的罕见变异来做到这一点。虽然自杀可能是精神疾病最可怕的方面，但对其生物学基础的研究相对较少。然而，家庭、双胞胎和收养研究表明，自杀行为有很大的可遗传成分。虽然有证据表明，这种遗传性在一定程度上是由情绪障碍的易感性造成的，但其他证据表明，可能存在独立的可遗传方面，可能跨越多种精神障碍。这种独立的特征被认为是攻击性和冲动的易感性，其遗传学研究主要集中在5-羟色胺能基因上。然而，很少对自杀表型进行系统的遗传学研究。在这项资助的第一次迭代中，我们进行了一项企图自杀的全基因组关联研究(GWAS)，它在rs300774的2p25上产生了关联信号(p=5.07×10-8)，这一发现处于全基因组意义的门槛(p&lt；5x10-8)。2p25上的相关SNPs落在一个包含ACP1基因的大连锁不平衡块中，ACP1基因在自杀完成的双相情感障碍(BP)患者中表达显著升高。此外，ACP1蛋白是一种与β-连环蛋白相互作用的酪氨酸磷酸酶。值得注意的是，与Wnt信号通路中的关键分子β-连环蛋白的连接，因为Wnt通路受到锂的正向调节，锂已被证明可以减少自杀行为。自杀行为和β-连环蛋白之间的联系得到了我们对自杀未遂的GWAS数据集的基因集丰富分析以及我们最初对39个碱基对的有自杀倾向的人和60个不有自杀的人的全外显子组测序的进一步支持。我们建议通过对2p25候选区域重新测序和对800名有自杀倾向的人和1,200名非有自杀倾向的人的整个外显子组数据进行二次分析来跟进这些发现，从而使我们能够在2p25、Wnt相关基因和整个基因组中寻找影响自杀行为风险的功能变异。为了实现这一目标，我们将利用包括分子遗传学、统计遗传学、生物信息学、神经生物学和精神病理学专家在内的优秀研究团队的多样化和互补性技能集。识别与自杀行为相关的候选基因和功能变异将对公众健康产生重大影响，因为它将为自杀行为的生物学基础提供新的见解，提供新的治疗靶点，并提供产生体内模型所需的数据，在其中测试治疗靶点。

DESCRIPTION (provided by applicant): This proposal aims to identify and characterize novel gene variants conferring susceptibility to suicidal behavior. We will do this both through intensive follow-up of a strongly implicated chromosomal region, and through performing the first ever exome-wide search for rare variants related to this phenotype. While suicidality is perhaps the most dreaded aspect of psychiatric disorders, relatively little research has been devoted to its biological basis. Yet family, twin, and adoption studies make clear that suicidal behavior has a substantial heritable component. While there is evidence that this heritability is accounted for in part by a liability to mood disorder, other evidence suggests an independent heritable facet that may cut across multiple psychiatric disorders. This independent feature has been hypothesized to be a liability to aggressiveness and impulsivity, the genetic study of which has focused on serotonergic genes. However, little systematic genetic investigation of the suicidality phenotype has been undertaken. In the first iteration of this grant, we conducted an attempted suicide genome-wide association study (GWAS), which generated an association signal on 2p25 at rs300774 (p=5.07 X 10-8), a finding that is on the threshold of genome-wide significance (p<5X10-8). The associated SNPs on 2p25 fall in a large linkage disequilibrium block that contains the ACP1 gene, whose expression is significantly elevated in bipolar disorder (BP) subjects who have completed suicide. Furthermore, the ACP1 protein is a tyrosine phosphatase that interacts with beta-catenin. The connection to beta-catenin, a key molecule in the Wnt signaling pathway, is noteworthy because the Wnt pathway is positively regulated by lithium, which has been shown to decrease suicidal behavior. The connection between suicidal behavior and beta-catenin was further supported by our gene set enrichment analysis of our attempted suicide GWAS dataset and by our initial whole-exome sequencing of 39 BP attempters and 60 BP non- attempters. We propose to follow up these findings by resequencing the 2p25 candidate region and by conducting a secondary analysis of whole-exome data from 800 attempters and 1,200 non-attempters, allowing us to search for functional variants influencing the risk for suicidal behavior on 2p25, in Wnt-related genes, and throughout the genome. To accomplish this, we will employ the diverse and complementary skill sets of an outstanding team of investigators including experts in molecular genetics, statistical genetics, bioinformatics, neurobiology, and psychopathology. The identification of candidate genes and functional variants associated with suicidal behavior would have a significant public health impact because it would provide new insights into the biological basis of suicidal behavior, provide new therapeutic targets, and provide the data needed to generate in vivo models in which to test therapeutic targets.